Yang Qi, Wang Jianwei, Liu Ran, Wang Zhiqiang, Li Yufeng, Zhang Yifan, Hao Xiaohua, Huang Yubo, Xie Wen, Wei Hongshan
Beijing Ditan Teaching Hospital, Peking University Health Science Center, Beijing, People's Republic of China.
Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China.
Drug Des Devel Ther. 2016 Jan 25;10:443-53. doi: 10.2147/DDDT.S92440. eCollection 2016.
Magnesium isoglycyrrhizinate (MGL) is a new stereoisomer of glycyrrhizic acid, which is clinically used as a hepatoprotective medicine with more potent effects and less side effects than glycyrrhizic acid. This study was designed to evaluate the protective effects and possible mechanism of MGL against concanavalin A (Con A)-induced autoimmune hepatitis. Hepatitis was induced by Con A in C57/6J mice with or without MGL administration; injury score and serum ALT were evaluated. The CD4(+) T-cells were isolated from splenocytes and challenged with Con A after coculturing with MGL. The injury score was significantly improved in MGL-treated mice after Con A challenging for 12 and 24 hours compared with those merely challenged with Con A. Similar trends were observed in the serum levels of ALT and AST. The most interesting result was that MGL administration significantly decreased the frequency of CD4(+)CD25(-)CD69(+) T-cells rather than CD4(+)CD25(+)CD69(+) T-cells in peripheral blood mononuclear cells, after Con A challenging 12 and 24 hours. Moreover, the serum ALT levels were markedly correlated with the frequency of CD4(+)CD25(-)CD69(+) cells, but only weakly correlated with CD4(+)CD25(+)CD69(+) cells in peripheral blood mononuclear cells. More importantly, MGL (5 mg/mL) almost completely eliminated the proliferation of the CD25(-)CD69(+) subset in primary CD4(+) T-cells after Con A challenge. Compared with merely Con A-challenged mice, those with MGL administration significantly demonstrated decreased NALP3, NLRP6, and caspase-3 expression, in which the NALP3 and caspase-3 downregulated in a dose-dependent manner. Our results indicate that MGL may have potential as a therapeutic agent in autoimmune hepatitis by ameliorating liver injury. Its molecular mechanism may be involved in inhibiting CD4(+)CD25(-)CD69(+) subset proliferation and downregulating inflammasome expression in liver tissue.
异甘草酸镁（MGL）是甘草酸的一种新的立体异构体，临床上用作保肝药物，其效果比甘草酸更强，副作用更少。本研究旨在评估MGL对刀豆蛋白A（Con A）诱导的自身免疫性肝炎的保护作用及可能机制。在C57/6J小鼠中，给予或不给予MGL的情况下，用Con A诱导肝炎；评估损伤评分和血清谷丙转氨酶（ALT）水平。从脾细胞中分离出CD4(+) T细胞，并在与MGL共培养后用Con A刺激。与仅用Con A刺激的小鼠相比，Con A刺激12小时和24小时后，MGL处理的小鼠损伤评分显著改善。血清ALT和谷草转氨酶（AST）水平也观察到类似趋势。最有趣的结果是，Con A刺激12小时和24小时后，给予MGL显著降低了外周血单个核细胞中CD4(+)CD25(-)CD69(+) T细胞的频率，而不是CD4(+)CD25(+)CD69(+) T细胞的频率。此外，血清ALT水平与外周血单个核细胞中CD4(+)CD25(-)CD69(+)细胞的频率显著相关，但与CD4(+)CD25(+)CD69(+)细胞的相关性较弱。更重要的是，Con A刺激后，MGL（5 mg/mL）几乎完全消除了原代CD4(+) T细胞中CD25(-)CD69(+)亚群的增殖。与仅用Con A刺激的小鼠相比，给予MGL的小鼠显著降低了NALP3、NLRP6和半胱天冬酶-3（caspase-3）的表达，其中NALP3和caspase-3以剂量依赖性方式下调。我们的结果表明，MGL可能通过改善肝损伤而具有作为自身免疫性肝炎治疗药物的潜力。其分子机制可能与抑制CD4(+)CD25(-)CD69(+)亚群增殖和下调肝组织中炎性小体表达有关。
